Isothiazoles



United States Patent 3,285,930 ISOTHIAZOLES Ralph P. Williams, Bartlesville, 0kla., assignor to Phillips Petroleum Company, a corporation of Delaware No Drawing. Filed Nov. 18, 1964, Ser. No. 412,238 3 Claims. (Cl. 260-302) This invention relates to novel isothiazoles and a process for their production. In one of its aspects, this invention relates to novel halo-substituted isothiazoles. In another aspect it relates to a process for the formation of halo-substituted isothiazoles.

The isothiazole ring structure has been postulated for many years, but until very recently attempts to synthesize this heterocyclic structure were unsuccessful. In 1959 it was reported by Adams and Slack in the Journal of the American Chemical Society that the isothiazole structure had been synthesized by a procedure involving the action of either chloroamine or peroxide compounds on beta-iminothiobutyramide. However, such starting materials are not readily available, and therefore the proc esses heretofore developed have not been too attractive for forming the heterocyclic ring.

It is an object of this invention to provide a novel process for the preparation of 3-haloisothiazoles. It is a further object to provide a method for the synthesis of these new compounds from readily available starting materials. A still further object of the invention is to provide 3-haloisothiazoles, 3,4-dihaloisothiazoles, and 3-halo- 4-nitroisothiazoles.

Other objects, aspects and the several advantages of the invention will be readily apparent to those skilled in the art from the description and the appended claims.

According to one aspect of this invention, 3-haloisothiazoles of the formula Y )CX at l wherein X is selected from the group consisting of chlorine and bromine, Y is selected from the group consisting of R and X and each R is selected from the group consisting of hydrogen and alkyl, aryl, cycloalkyl and combinations of these radicals, such as aralkyl and alkaryl, containing from 1 to 10 carbon atoms, inclusive, are produced by contacting a 3-mercaptopropionitrile of the formula wherein R is as previously defined with elemental chlorine or bromine.

Compounds which are provided in accordance with this invention include 3-chloroisothiazole, 3,4-dichloroisothiazole, 3-bromoisothi-azole, 3-bromo-5-rnethylisothiazole, 3- choro 4,5-dimethylisothiazole, 3-chloro-4-n-butylisothiazole, 3-bromo-5-isooctylisot-hiazole, 3-chloro-4,5-di-n-decylisothiazole, 3-bromo5-phenylisothiazole, 3-chloro-4- benzylisothiazole, 3 brorno-S-cyclohexylisothiazole, 3- chloro 4-(4-phenylbutyl)isothiazole, 3,4-dibromo-5-(4- butylphenyl)isothiazole, 3-chloro-5-cyclodecylisothiazole, and 3bromo-4-phenyl-5-(4-butylcyclohexyl)isothiazole.

In addition, nitrated products according to another aspect of this invention include 3-chloro-4-nitroisothiazole, 3-bromo-4-nitro-5-ethylisothiazole, 3-bromo-4-nitro-5-(2- methylcyclohexyl)isothiazole, 3-chloro-4-nitro-5-n-decylisothiazole, and the like.

Examples of 3-mercaptopropionitriles which are employed as reactants in the process of this invention are 3- 3,285,930- Patented Nov. 15, 1966 mercaptopropionitrile, 3-mercaptobutyronitrile, 2-methyl- S-mercaptopropionitrile, 3-mercaptocapronitrile, 3-mercaptolauronitrile, 3-mercaptotridecanenitrile, 3-mercapto- 2-decyltridecanenitrile, 2-cyclohexyl-3-rnercaptopropionitrile, 3-mercapto-3-phenylpropionitrile, 3-mercapto-3-cyclopentyl-Z-tert-butylpropionitrile, 3-mercapto-4-phenylbutyronitrile, 3 mercapto-3-(4-n-butylphenyl)pronionitrile, 3 mercapto-5-(Z-methylcyclohexyl)valeronitrile and the like.

The process of this invention is carried out by contacting one of the above-defined 3-mercaptopropionitriles with elemental chlorine or elemental bromine in the presence of a diluent which is a solvent for the nitrile compound and which is non-reactive with the nitrile and the halogen. The reaction is carried out at a temperature generally ranging from ---25 to 0., preferably below 50 C. The reaction time can vary widely and can range from a few minutes to several days, but will generally be less than eight hours.

Some examples of solvents which are inert with respect to the reactants and which can be advantageously employed are carbon tetrachloride, chloroform, tetrachloroethane, and the like. The amount of diluent which is used can vary widely but will generally range from about 1 to about 10 ml. per gram of 3-mercaptopropionitrile reactant.

The mol ratio of elemental chlorine or elemental bromine to mercaptonitrile reactant can also vary widely but will generally range from 0.5/1 to 5/1, preferably from 1/1 to 3/ 1.

The reaction is conveniently carried out by contacting a solution of nitrile in one of the above-defined diluents at the specified temperature with the elemental chlorine or bromine. The elemental chlorine can be bubbled into the solution at a rate such that it does not pass through the solution too rapidly for the reaction to occur.

The 3-haloisothiazole product can be recovered by a variety of procedures. One particularly convenient method for recovering the product is to dispel dissolved HCl or HBr, e.g. by heating. The reaction diluent can then be removed by any suitable procedure, such as vacuum stripping, after which the remaining material can be worked up by distillation, solvent extraction, crystallization, and other well-known procedures. One particularly suitable method is to distill the material remaining after solvent stripping and to dissolve the distillate in a suitable solvent followed by washing with dilute aqueous base (10 percent aqueous Na CO for example) and water to remove dissolved hydrogen chloride or hydrogen bromide, and then to recover the S-haloisothiazole by fractionating the organic phase. The residue from first distillation can be treated to recover further amounts of the product by steam distillation followed by solvent extraction. In another method of operation, the product can be recovered directly from the reaction mixture by steam distillation followed by solvent extraction and final distillation.

The 3-mercaptopropionitrile reactants of this invention are readily available materials and can be prepared, for example, by reacting hydrogen sulfide with acrylonitrile in the presence of a base to form the 3-mercaptopropionitrile.

In a further aspect of this invention, the 3-haloisothiazole compounds are nitrated to form 4-nitro-3-haloisothiazoles. Conventional nitrating agents can be utilized, i.e., reaction of the 3-haloisothiazole with a nitrating agent such as fuming nitric acid, preferably in concentrated sulfuric acid. Such nitrations are preferably effected at temperatures below 25 C. using reaction times ranging from a few minutes to several :days, generally less than ten hours. The mol ratio of nitrating agent to 3-haloisothiazole will generally range from about 0.5/1 to 2/1 and more usually will approximately 1/1. Recovery of the Q thus produced 4-nitro-3-haloisothiaz0les can be effected by the techniques described previously for recovery of the 3-haloisothiazole product.

The 3-haloisothiazoles, 3,4-dihaloisothiazoles and 3- 4 EXAMPLE II The procedure of Example I was repeated except that 3- mercaptobutyronitrile was employed. The product was analyzed and found to be 3-cl1loro-5-methylisothiazole.

halo-4-nitroisothiazoles of this invention are useful as 5 pesticides and as intermediates for the preparation of maie l gg g cap gi z g igg terials useful as pesticides, pharmaceuticals and the like. to 1 5 r 3 s g f g magntaim The compounds of this invention are particularly active in the rature 5 i 284 mols) of against chewing-type insects of the family Insecta Orthopchglorine g Bubbled int tbs 1 one hour tera, which includes locusts, grasshoppers, crickets and the 10 o l O u 1 a f 1ik6 per1od. The solution turned yellow when 73.5 grams 0 The following specific examples are intended to illusq i had been ad.ded and Temamed. yellow dunng the trate the preparation of 3-haloisothiazoles according to the gi p gi gz i gg g 3f g g i g g' YZ Z Q has}? inventive process, but it is not intended that the invention c onne e rge e s S y be limited to the specific features shown therein. to to room.temperature followmg which the sohltlon was stirred for SIX hours and allowed to stand overmght. EXAMPLE I The following day the solution was heated briefly to its A series of five runs was Carried out in which 3 mercap boiling point to expel dissolved I-ICl after which it was topropionitrile was reacted with elemental chlorine accordcholed f extracted two tunes wlth 2 water one ing to the process of this invention. In each of these runs, h with 100 10 percehhhy welfght aqueous P a Chlorine/3 me.rcaptopmpionitrfle mol ratio of from slum carbonate, and two more tlmes W1th 200 ml water in proximately l/1 to 3/1 was employed. In each of the h wish The orgahlc Phase was then dned Over a runs, the 3-mercaptopropionitrile was dissolved in chlorohhsmm Sulfate and the filtrate was cohchhtrat?d by Strip form and the resulting solution was cooled to 10 to P Q h solvent on a t m ath under aspirator vacu- 20 C. and contacted with the desired amount of chloh Yleldmg 266 g m of d hqmd reslduefine by bubbling in the chlorine at a rate 510W enough to s1due was steam distilled until about 1500 ml of dlstillate allow the temperature to be maintained at C or was taken overhead. The organic phase in the distillate below. After all the chlorine had been added, the mixture and two 9 chlhroform extracts of the aqueous Phase was allowed to warm to approximately 10 C. while stirwere Chmhlhed: dned W Mgs04 and concentrated to ring. The reaction solution was then warmed slowly to l9h-3 grams h evaporahoh' about room temperature after which the mixture was re- This matenal was then fmfhohated through an 8 f fl d at about 60 to C for 30 minutes by 36" Hypercal column to yreld 143.8 grams of material The chloroform was then stripped from the reaction 'bolhng at 4 P' Y absolut? Pressure and mixture under aspirator vacuum leaving a dark liquid regrams of material holhng to 68 at 4 sidue which was distilled through a 10 Vigreux column marcufy 31350111? P I to obtain a concentrate of the product. This concentrate The lower bolllng fffactlon Was examlhed 7y nllclfiaf was then refractionated through a 20" vacuum column to magnetic resonance, w nfi d the ls a n obtain a closer boiling cut of the product. The details of Structure and Confirmed the P 6561196 0116 y P 'P these fi runs are given i bl L and one hydrogen atom on the lsothiazole ring. Since Table 1 Charge Chlorine Chlo- Grams Refractionated Material 3-mercapto Charge rine Dis- Yield Run propionitrile M]. Additill- B.P. C. 3 -chlo ro- No. CHC]; tion able at (X) 71-1, Mols isothia- 71,,10

Time, Prodmm. Hg 13.1. C. Press Grams 3-chlor0- zole Mol Grams Mols Grams Mols Min- 1101; iSOthiap nt utcs zole \J 104 1. 39 144 2.0 1,000 is 20.9 55-57 at 19.- 1. 5375 104 1.89 425 0.0 1,000 90 172.4 57- s at 1.5555 68-70 25 93.7 0. 784 41.5 i sggs- 174 2. 0 291 4.1 1,000 35 103.9 48-00 a 4-20. 1.553s 05-70 25 110.5 0.975 48.6 1 5%; 435 5. 0 730 10.3 1,750 00 449.1 59-74 at 04. 5-075 24.5 390. 6 3.32 1 5535- 1 Not Reiractionated. 1 Not Measured.

The product from Run 1 of Table I was subjected to the methyl group in the starting reactant 3-mercaptoelemental analysis, the results of which are as follows: butyronitrile was located on the carbon adjacent the sulfur atom, the structure of this material is thus 3-chloro- Element Calculated weight Found, Weight 6 r 5methylisothiazole- Percent for CsHzClNS Percent 0 An elemental analysi of the 3-chloro-5-methylisothiazole gave the following results: Carbon 30. 2 30. 1 Hydrogen 1. 7 1.77 Chlorine 29. 6 29. 2 Element Calculated Weight Found, weight g1 uiltfrltlirgem g 2 percent for C4H4C1NS percent 35.90 35.1 This matenal was analyzed by nuclear ma gnetic resonance i 3- 6 which confirmed the ring structure and indicated th pres- $12 $33 ence of two hydrogen atoms which were located on ad- 2100 jacent carbon atoms.

Nuclear magnetic resonance of the higher boiling fraction confirmed its structure to be a dichloromethylisothiazole. Thus this compound was 3,4-dichloro-5-methylisothiazole. An elemental analysis of this material gave the following results:

In an attempt to see if the procedure of this invention could be employed for ring closure of 4-mercaptobutyronitrile, this compound was reacted with chlorine by the procedure of Examples I and II. No product was obtained, as the material decomposed when it was attempted to distill product from the reaction solution.

EXAMPLE IV The 3-ch1oroisothiazole from Run 5 of Table I was nitrated by the following procedure.

In this run, 24 grams (0.2 mol) of the 3-chloroisothiazole from Run 5 was stirred slowly into 126 ml. of concentrated sulfuric acid which had been previously cooled to 15 C. The solution temperature was kept below 30 C. while adding the 3-chloroisothiazole. The resulting solution was then cooled to 5 C. and 12 ml. of fuming nitric acid (density 1.49-1.50) was added to the solution in portions while cooling, keeping the temperature below C. The stirred mixture was slowly heated to 98 C. on a steam bath and maintained at 94-98 C. for 4.3 hours. The material was then cooled and poured over 300 grams of ice. 700 ml. of water wa then added to the resulting mixture, and the mixture was then extracted three times with 150 m1. ether in each extraction. The combined extracts were then washed three times with 50 ml. portions of water, one time with 100 ml. of 5 weight percent aqueous sodium bicarbonate and two times with 50 ml. portions of water. The ether phase was then dried, filtered, and the ether was stripped oil? under vacuum. The remaining material was distilled through a short path column. The charge to the column was 26.2 grams and 16 grams of material boiling from 103.5" C. at 3 mm. mercury absolute pressure to 93 C. at 0.5 mm. mercury was obtained, refratcive index n 1.6087-L609Z.

An elemental analysis of this material gave the following results:

Not Measured.

The above results are consistent with the nitrated material being 3-chloro-4-nitroisothiazole.

Reasonable variations and modifications of this invention can be made, or followed, in view of the foregoing, without departing from the spirit or scope thereof.

I claim:

1. A process for preparing compounds of the formula wherein R is a member selected from the group consisting of hydrogen and alkyl, aryl, cycloalkyl, aralkyl and alkaryl radicals containing from 1 to 10 carbon atoms, X is a member selected from the group consisting of chlorine and bromine, and Y is a member of the group consisting of chlorine, bromine, alkyl, aryl, cycloallcyl, aralkyl and alkaryl containing from 1 to 10 carbon atoms, comprising contacting with a compound of the group consisting of elemental chlorine and elemental bromine a 3- mercaptoprop-ionitrile of the formula of halogen to mercaptonitrile is in the range of 0.5/1 to 5/ 1.

References Cited by the Examiner FOREIGN PATENTS 629,580 10/ 1963 Belgium.

OTHER REFERENCES Adams et al.: J. Chem. Soc. (London), 3061-72.

Huebenett et al., Angew. Chem, volume (1963), pp. 1189-93.

ALEX MAZEL, Primary Examiner. HENRY R. JILES, Examiner. RICHARD J. GALLAGHER, Assistant Examiner. 

1. A PROCESS FOR PREPARING COMPOUNDS OF THE FORMULA 